Metalloprotease inhibitors are cellular inhibitors of the Matrix metalloproteinases (MMPs).[1] MMPs belong to a family of zinc-dependent neutral endopeptidases.[2] These enzymes have the ability to break down connective tissue. The expression of MMPs is increased in various pathological conditions like inflammatory conditions, metabolic bone disease, to cancer invasion, metastasis and angiogenesis.
Examples of diseases are periodontitis, hepatitis, glomerulonephritis, atherosclerosis, emphysema, asthma, autoimmune disorders of skin and dermal photoaging, rheumatoid arthritis, osteoarthritis, multiple sclerosis, Alzheimer's disease, chronic ulcerations, uterine involution, corneal epithelial defects, bone resorption and tumor progression and metastasis.[2][3] Due to the role of MMPs in pathological conditions, inhibitors of MMPs may have therapeutic potential.[3] Several other proteins have similar inhibitory effects, however none as effective (netrins, procollagen C-terminal proteinase enhancer (PCPE), reversion-inducing cysteine-rich protein with Kazal motifs (RECK) and tissue factor pathway inhibitor (TFPI-2)). They might have other biological activities which have yet been fully characterised.[4]
MMP inhibitors can broadly be subdivided into non-synthetic (e.g. endogenous) or synthetic.[2] Several potent MMP inhibitors have been identified, including hydroxymates, thiols, carbamoylphosphonates, hydroxyureas, hydrazines, β-lactams, squaric acids and nitrogenous ligands.[5]
There are three classes of commonly used inhibitors for metalloproteinases.
In vitro, EDTA, 1,10-phenanthroline and other chelating compounds lower the concentration of metal to the point where the metal is removed from the enzyme active site.
Classical lock and key inhibitors such as phosphoramidon and bestatin bind tightly by approximating the transition state of the hydrolysis of the peptide, preventing it from acting on other substrates.
Protein inhibitors such as α2-macroglobulin are known to work with metalloproteinases.
^Frederick, W. (1999). "Matrix Metalloproteinase Inhibition: From The Jurassic To The Third Millennium". Ann N Y Acad Sci. 878 (1): 388–403. Bibcode:1999NYASA.878..388W. doi:10.1111/j.1749-6632.1999.tb07697.x. PMID 10415743. S2CID 29467651.
^ abcAcharya, M. R.; Venitz, J.; Figg, W. D.; Sparreboom, A. (2004). "Chemically modified tetracyclines as inhibitors of matrix metalloproteinases". Drug Resistance Updates. 7 (3): 195–208. doi:10.1016/j.drup.2004.04.002. PMID 15296861.
^ abWhittaker, Mark; Ayscough, Andrew (2001). "Matrix metalloproteinases and their inhibitors- current status and future challenges". Celltransmissions. 17 (1): 3–14.
^Durrant, J. D.; de Oliveira, C. A. F.; McCammon, J. A. (2011). "Pyrone-Based Inhibitors of Metalloproteinase Types 2 and 3 May Work as Conformation-Selective Inhibitors". Chemical Biology & Drug Design. 78 (2): 191–198. doi:10.1111/j.1747-0285.2011.01148.x. PMC 3135671. PMID 21609408.
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